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- PDB-4lm3: Crystal structure of PDE10A2 with fragment ZT464 -

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Basic information

Entry
Database: PDB / ID: 4lm3
TitleCrystal structure of PDE10A2 with fragment ZT464
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / fragment screening / hydrolase / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cGMP binding ...3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / : / cAMP binding / G alpha (s) signalling events / glutamatergic synapse / metal ion binding / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / GAF domain ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / GAF domain / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / GAF-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone / NICKEL (II) ION / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.49 Å
AuthorsSridhar, V. / Badger, J. / Logan, C. / Chie-Leon, B. / Nienaber, V.
CitationJournal: J Biomol Screen / Year: 2014
Title: Identification and Optimization of PDE10A Inhibitors Using Fragment-Based Screening by Nanocalorimetry and X-ray Crystallography.
Authors: Recht, M.I. / Sridhar, V. / Badger, J. / Bounaud, P.Y. / Logan, C. / Chie-Leon, B. / Nienaber, V. / Torres, F.E.
History
DepositionJul 9, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 26, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 26, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,55810
Polymers78,9582
Non-polymers5998
Water9,368520
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8996
Polymers39,4791
Non-polymers4205
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,6594
Polymers39,4791
Non-polymers1793
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2150 Å2
ΔGint-13 kcal/mol
Surface area27800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.893, 82.146, 155.085
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A


Mass: 39479.242 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, UNP residues 439-779
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-9ZE / 1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethanone


Mass: 178.185 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H10O3
#3: Chemical
ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ni
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 520 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE FOUR DIVALENT CATIONS ARE REPRESENTED BY NI BUT THIS IDENTIFICATION IS SPECULATIVE

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.09 Å3/Da / Density % sol: 41.24 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 18% PEG4450, 0.2m calcium acetate, 50mM BME, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Jul 16, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.49→50 Å / Num. all: 108380 / Num. obs: 108380 / % possible obs: 99.5 % / Observed criterion σ(F): -4 / Observed criterion σ(I): -4 / Redundancy: 5.9 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 24.6
Reflection shellResolution: 1.49→1.54 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.578 / Mean I/σ(I) obs: 2.7 / Num. unique all: 10544 / % possible all: 98.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.5.0072refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2OUR

2our


Resolution: 1.49→38.77 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.957 / SU B: 1.702 / SU ML: 0.062 / Cross valid method: THROUGHOUT / ESU R: 0.082 / ESU R Free: 0.081 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.22354 5407 5 %RANDOM
Rwork0.19858 ---
obs0.19982 102889 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.273 Å2
Baniso -1Baniso -2Baniso -3
1-0.46 Å20 Å20 Å2
2---0.27 Å20 Å2
3----0.19 Å2
Refinement stepCycle: LAST / Resolution: 1.49→38.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5246 0 29 520 5795
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0225460
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2751.957395
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8765656
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.94224.04250
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.62415958
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7661528
X-RAY DIFFRACTIONr_chiral_restr0.0870.2821
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214082
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.93623283
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.5612.55332
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.05232177
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.2244.52063
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.49→1.529 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.403 394
Rwork0.398 7219

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